No clear molecular target could, however, be identified. Very recently, hyperforin has been shown to behave also as a potent inhibitor of lymphangiogenesis. Hyperforinis a prenylated phloroglucinol derivative that consists of a phloroglucinol skeleton derivatized with lipophilic isoprene chains. A shortcoming of hyperforin is its chemical and metabolic instability, bound to the presence of reacting functional groups, expressed by the enolized and oxidation �Cprone b-diketone moiety and the prenyl side chains. To overcome these issues, we have investigated the antiangiogenic properties of a series of stable derivatives obtained by oxidative modification of the natural product. Our results throw light on the role of the enolized b-dicarbonyl system contained in the structure of hyperforin and identify two new promising antiangiogenic compounds, one of them even more potent than hyperforin. We have previously shown that hyperforin is a potent multitarget antiangiogenic compound. This observations adds to the antimetastasic effect previously reported and was confirmed by other authors, using stable salts of the bioactive compound. In the present study, we have used dicyclohexylammonium hyperforinatein Figure 1) as a stable form of hyperforin maintaining its bioactivity. In fact, our results with compoundas a positive control compound show similar results to those published for the free acid form at slightly lower concentrations, as expected for a stabilized form of the compound. Hyperforin instability is due to the contemporary presence of fastly reacting functional groups: an enolized b-diketone moiety, apparently present in solution as 7-hydroxy, 9-keto tautomer due to the formation of a Nilotinib hydrogen bonding between the ketone in position 1 and the 7-hydroxy group, and the close proximity of this latter to the double bond of the 6- prenyl group. In addition, carbon 8 is strongly nucleophilic, and easily oxidized. Both these characteristics induce a fast BYL719 reactivity toward oxidizing agents, including light, and lead to unexpected derivatives, some of which also accumulate in the extracts, like compoundsand. One of the major degradation routes for hyperforin is the formation of furan derivatives by mutual oxidative interaction of the enol moiety and the prenyl chains, irreversibly blocking the 7hydroxy in an ether linkage. In compound, a hemiacetal species is formed by the introduction of an electrophilic oxygen at C8, which in situ reacts with the spatially faced carbonyl group at C1. Compoundsandwere chosen among the different oxidized derivatives to be investigated for their antiangiogenic potential. They represent very stable hyperforin derivatives, where the overall molecular structure is preserved but the enolized bdiketone functionality has collapsed to form furan rings. In previous works, compoundsandhave shown to be less active than hyperforin in vitro as inhibitors of synaptosomal serotonin reuptake, but they had a comparable effect as growth inhibitors of P. falciparum cultures, although showing less toxicity. Oxidized hyperforin derivativesandhave also shown to be equally or more potent than hyperforin as inhibitors of 5lipooxygenase activity. In addition, furohyperforins are also reported to potently inhibit CYP3A4 enzyme activitythus inferring the enolized b-diketone moiety a significant role in modulating many kinds of activities. Our results herein presented altogether show that these compounds behave as much less potent antiangiogenic compounds than hyperforin. This is evidenced by the limited activity shown in all the panel of tests used.